Treatment of hypertension with 2-hydroxy (or amino) - 4,5 - dihydroxyphenethylamine derivatives



TREATMENT OF HYPERTENSION WITH Z-HY- DROXY (R AMINO) 4.5 DIHYDROXYPHEN-ETHYLAMINE DERIVATIVES Clement A. Stone, Blue Bell, Pa., assignor toMerck & (30.,

Inc., Rahway, N..I., a corporation of New Jersey No Drawing.Continuation-impart of application Ser. No. 205,227, June 26, 1%2. Thisapplication Sept. 21, 1965, Ser. No. 489,058

Int. Cl. A611: 27/00 U.S. Cl. 424330 4 Claims ABSTRACT OF THE DISCLOSUREA method of treatment of hypertension in warmblooded vertebrates isdescribed wherein 2-hydroxy (or amino)-4,5-dihydroxy phenethylamine,optionally substituted with a methyl or ethyl group on the a-carbon isadministered by one of several different routes.

This invention relates to pharmaceutical compositions and particularlyto compositions for the reduction of blood pressure in hypertensives.

This application is a continuation-in-part of copending application,Ser. No. 205,227, filed June 26, 1962, now abandoned.

Hypertension is a disorder in which the arterioles exhibit abnormalresistance to the flow of blood, usually associated with an abnormalincrease in systolic, diastolic and mean arterial pressures, andsymptomatically evidenced by fatigue, nervousness, dizziness,palpitation, insomnia, weakness and headaches at some time in the courseof the disorder. Angina pectoris and myocardial infarction due tocoronary artery disease are frequent complications, while congestivefailure may occur as a result of coronary insufficiency, or cardiachypertrophy, or both factors in combination. It is a serious disease.For example, in humans, average life expectancy probably is close totwenty years from onset, with extremes of several years or severaldecades.

Etiologically, the cause of hypertension is not known and consequently,its therapy is uncertain. There is no treatment now known thatconsistently and completely reverses the cause of hypertesion. Manysymptoms of uncomplicated hypertension respond to the combination ofreassurance by the doctor and time, but in most instances medicinaladministration must be undertaken. Many antihypertensive drugs are nowavailable, such as the alkaloids of rauwolfia, the thiazides andganglionic blocking agents, e.g., mecamylamine, but they are notuniformly effective in their action. Their degree of effectiveness andthe severity of induced side reactions varies considerably from patientto patient. Consequently, an additional hypertensive agent offers thepossibility of filling the gaps which exist at present among theavailable medicines.

In accordance with the present invention, it has been found that highblood pressure is reduced by the administration of a compound selectedfrom those represented by the formula States Patent 0 3,457,354 PatentedJuly 22, 1969 vention. For oral administration, the compound may simplybe placed in gelatin capsules so that one or two of them will carry aunitary dosage into the patient. Or, tablets may be made up, usingconventional tableting agents and procedures, so that one or two tabletswill contain the amount of active compound to constitute a unitarydosage. In addition, the invention contemplates pharmaceuticalpreparations in the forms of elixirs and aqueous solutions andsuspensions of such concentrations that the usual teaspoonful or twowill serve as a unit dose.

Although the hypotensive agents of this invention find particularutility in the treatment of hypertensive disorders in man, these agents,in addition, have use in the veterinary field for treatment of bloodpressure abnormalities in domestic warm-blooded vertebrates. Forexample, the hypotensive compositions of this invention find particularuse in the treatment of hypertensive disorders in domestic fowl, such asturkeys, or mammals, such as domestic large animals, for example, inhorses to control nosebleed, or to control capillary bleeding duringsurgery in cats, dogs and other small animals.

The daily dose for humans is from to 200 milligrams and this preferablyis given to the patient in fractional amounts at intervals throughoutthe day. For example, a capsule would contain ten milligrams of thecompound and one or two of them would be taken at a time, from one tofour times a day. If larger daily doses are required, it would bepreferable to put into a single capsule up to 200 mg. of the compound.This plan would be carried out with tablets although the smaller dosagesingle tablet could contain say 20 to milligrams as the tablet can bestored to break it up into two or four pieces to be taken at a time. Inlike manner a conventional liquid pharmaceutical preparation may beprepared either for needle injection or oral consumption. Theconcentration per ml. or liquid ounce may be varied so that the doctorcan adjust the dosage for the individual patient.

Dosages for veterinary administtation vary, depending on the animal tobe treated, but in general, fall in a range of about 0.1 to 10 mg./kg.per day. Formulations, as discussed above, are employed.

The compounds in which R is hydrogen are known in the art and may bemade by the process described by J. Harley-Mason in J. Chem. Soc.(1953), page 200. The compounds in which R is methyl or ethyl are newand therefore constitute a distinct part of this invention.

Processes for making them will be clear from the following examples.

EXAMPLE I.2 AMINO 4,5 DIHYDROXY a METHYLPHENETHYLAMINE DIHYDROCHLO- RIDE3,4 dimethoxy a methylphenethylamine (4.0 g., 0.0205 mole) was addeddropwise to a mixture of 32 ml. of concentrated nitric acid (d. 1.4) and12 ml. of water, while stirring and maintaining the temperature at 12-15 C. by external cooling. When the addition was complete, the solutionwas stirred at 1015 C. for 3 hours. After standing an additional 30minutes at this temperature, it was cooled to 0 C. and poured into ml.of an ice-water mixture. The pale yellow solid that separated wascollected and air dried.

The solid, the nitrate salt of2-nitro-4,5-dimethoxy-otmethylphenethylamine was suspended in water, themixture rendered alkaline with sodium carbonate and the base extractedinto chloroform. After washing with water, the chloroform extract wasdried over sodium sulfate and the solvent distilled under reducedpressure. The brown oily residue solidified on cooling.

The base, 2.72 g. was dissolved in absolute alcohol and the solutiontreated with 3.5 ml. of a 4.1 N solution of dry hydrogen chloride inabsolute alcohol. The hydrochloride was recrystallized from amethanol-ether mixture and twice from ethanol-ether mixtures to giveproduct, M.P. 215.5-2165 C.

Analysis.-Calcd. for C H O N -HCl: C, 47.74; H, 6.19; N, 10.13. Found:C, 47.75; H, 6.22; N, 9.88

The base was prepared from the hydrochloride by dissolving the salt inwater, rendering the solution alkaline with sodium hydroxide andextracting the base into benzene. Distillation of the benzene left theyellow base that crystallized on cooling and melted at 81.5-84.5" C.

Step B.-Preparation of 2amino-4,5-dimethoxyamethylphenethylaminedihydrochloride The product of Step A, 2-nitro-4,5-dimethoxy-a-methylphenethylamine (35.5 g., 0.148 mole) was dissolved in 200 ml. ofabsolute alcohol and hydrogenated over Raney nickel at 22 C. with aninitial hydrogen pressure of 42 pounds per square inch. The catalyst wasseparated by filtration through a mat of diatomaceous earth. Thefiltrate was cooled in an ice-bath and a stream of dry hydrogen chloridepassed in until an excess was present. Ether was added and theprecipitated solid was collected and recrystallized from amethanol-ether mixture. The hydrochloride of2-amino-4,S-dimethoxy-a-methylphenethylamine was obtained as a tancrystalline solid. The M.P. was highly dependent on the rate of heating.After drying over phosphorus pentoxide at room temperature, analyseswere consistent with a formula containing methanol and water ofcrystallization.

Analysis.-Calcd. for C11H1302N2'2HC1% CH3OH' /2 H O: C, 44.81; H, 7.52;N, 9.09. Found: C, 44.67; H, 7.73; N, 8.96.

Step C.Preparation of 2-amino-4,5-dihydroxy-a-methylphenethylaminedihydrochloride The product of Step B (7.92 g., 0.028 mole) was dividedinto four equal portions. Each was dissolved in 20 ml. of concentratedhydrochloric acid. These solutions were sealed in glass tubes and heatedto 150 C. for 2 hours. The tubes were cooled, opened, and the liquiddistilled under reduced pressure from a bath at 4555 C. in an atmosphereof nitrogen. After concentrating the solution to near dryness, alcoholwas added and the solution cooled. The gray crystalline product,obtained in two crops weighed 5.83 g. Recrystallization from mixtures ofmethanol and ether gave the product, M.P., 240241 C. with decomposition.

Analysis.-Calcd. for C H O N -2HCl: C, 42.36; H, 6.32; N, 10.98. Found:C, 42.34; H, 6.24; N, 10.89.

EXAMPLE II.2 AMINO 4,5 DIHYDROXY a ETHYLPHENETHYLAMINE DIHYDROCHLORIDEBy using 3,4 dimethoxy a ethylphenethylamine in place of 3,4 dimethoxyoz methylphenethylamine and following the process of Example I, thiscompound was obtained.

EXAMPLE III.-2,4,5 TRIHYDROXY oz METHYL- PHENETHYLAMINE StepA.Preparation of 1 (2,4,5 trimethoxyphenyl)- 2-oximino propane2,4,S-trimethoxyphenylacetone (25.0 g., 0.111 mole), hydroxylaminehydrochloride (9.3 g., 0.134 mole) and potassium acetate (15.6 g., 0.158mole) were added to 400 ml. of 70% ethyl alcohol contained in a literflask fitted with a reflux condenser. The mixture was heated on a steambath to gentle refiux for 3% hours. The cooled reaction mixture wasevaporated to dryness under reduced pressure and the residue extractedfour times with 150 ml. portions of benzene. The combined benzeneextracts were washed twice with 75 ml. portions of water and then driedover anhydrous MgSO Evaporation of the benzene under reduced pressureleft a tan oil (26.8 g), which was redissolved in benzene and diluted bydropwise addition of petroleum ether until white crystals appeared.After completion of the crystallization, filtration yielded 20.1 g.;M.P. -85 C. Recrystallization from benzene-petroleum ether yielded 18.1g. white crystals, MP. 91.5- 93 C.

Analysis.-Calcd. for C12H17O4NZ C, 60.23; H, 7.16; N, 5.85. Found: C,60.22; H, 7.21; N, 5.84.

Step B.Preparation of 2,4,5 trimethoxy a methylphenethylaminehydrochloride 1 (2,4,5 trimethoxyphenyl) 2 oximino propane (18.1 g.,0.075 mole) was dissolved in 200 ml. of methyl alcohol and subjected tohydrogenation in the presence of one teaspoon of Raney nickel at C. and1700 p.s.i. Observed pressure drop at 20 C. was 100 p.s.i.

The reaction mixture was filtered to removethe catalyst and the solventevaporated under reduced pressure to leave a dark yellow residue. Theresidual oil was dissolved in excess ether and sufficient 4 N alcoholichydrochloric acid added to precipitate the hydrochloride of the product.The amine hydrochloride was filtered and washed with ether. It weighed17.5 g. and melted at 178181 C. Recrystallization from isopropyl alcoholyielded 14.9 g. of white crystals, M.P. 186.5-l87.2 C.

Analysis.Calcd. for C H O NCl: C, 55.06; H, 7.70; N, 5.35. Found afterdrying in vacuo/P O at 100 C. for 5 hours; C, 55.26; H, 7.71; N, 5.41.

Step C.-Preparation of 2,4,5 -trihydroxy-a-methylphenethylaminehydrobromide 2,4,5 trimethoxy a methylphenethylatnine hydrochloride (3.0g., 0.0115 mole), 65 ml. of bromine free 48% hydrobromic acid and 65 ml.of glacial acetic acid were mixed under an N atmosphere and refluxed for16 hours under N The solvent was removed under reduced pressure and hotwater bath. Methyl alcohol containing S0 was added to the residue andremoved under reduced pressure. The latter process was repeated and theresidue dissolved in 50 ml. of Water containing S0 The solution wastreated with acid washed Norit and filtered through an acid washed Noritpad on a porcelain filter while protecting it from oxygen with anitrogen atmosphere. The filtrate was evaporated to dryness underreduced pressure and hot water bath to leave a glassy residue. Thismaterial was treated with ethyl alcohol containing S0 four times and thesolvent removed under reduced pressure each time. Repeated attempts toobtain a crystalline material from butyl alcohol-ether wereunsuccessful.

Analysis.Calcd. for C H O NBr: C, 40.92; H, 5.34; N, 5.30; Br, 30.26.Found after drying in vacuo over phosphorus pentoxide at C. for 21hours: C, 42.22; H, 5.58; N, 5.32; Br, 29.20; OCH;,, 0.00.

Paper chromatography in sec-butyl alcohol (75%) formic acid (15%), H 0(10%) (S0 atmosphere) (ascending) showed a major component of R 0.29 anda minor component of R 0.41 which appeared to be forming during thecourse of the chromatography.

The glassy hydrobromide crystallized after several months refrigerationunder nitrogen.

EXAMPLE IV.-2,4,S-TRIHYDROXY-u-ETHYL- PHENETHYLAMINE HY DROBROMIDE StepA.Prepa1ati0n of 1-(2,4,5-trimethoxyphenyl)-2- nitrobutene-l 2,4,5-trimethoxybenzaldehyde (30.0 g., 0.152 mole), n-butyl amine (3.2 g.,0.044 mole), l-nitropropane (15.7 g., 0.176 mole) and 50 ml. of toluenewere placed in a 500 ml. flask fitted with a stirrer, reflux condenserand Dean-Stark water collecting apparatus. The dark solution was heatedfor 20 hours while stirring and refluxing. On cooling an orange solidseparated and was collected by filtration-28.6 g.M.P. 97-109 C. Thesolid was recrystallized from 300 ml. of methyl alcohol to yield 22.8 g.of material melting at 112113 C.

AnaZysis.-Calcd. for C13H17O5NZ C, 58.41; H, 6.41; N, 5.24. Found: C,58.63; H, 6.63; N, 5.42.

Step B.Preparation of 2,4,5-trimethoxy-u-ethylphenethylaminehydrochloride A solution of 1 (2,4,5 trimethoxyphenyl) 2 nitrobutene 1(26.7 g., 0.1 mole) dissolved in 250 ml. of dry THF was added dropwiseto a stirring, refluxing solution of lithium aluminum hydride (18 g.) intwo liters of reagent grade ether over a period of 1 /2 hours. Thereaction mixture was refluxed with stirring and calcium chloride tubeprotection for an additional two to three hours and the excess lithiumaluminum chloride decomposed by dropwise addition of ethyl alcohol.Sodium potassium tartrate solution (600 ml. of 40%) and 250 ml. of waterwere added. The mixture was transferred to a large separatory funnel andthe ether phase separated. The aqueous phase was extracted three timeswith ether and the combined ether phase dried over potassium hydroxide.Evaporation of the ether under reduced pressure left a white oily solidwhich was dissolved in alcohol, treated with charcoal and filtered. Theclarified alcohol solution was treated with 30 ml. of 5.8 N alcoholichydrochloric acid and the solution diluted with ether and chilled togive white crystals-l6.0 g.M.P. 206- 207 C.

Analysis.Calcd. for C H O NCl: C, 56.61; H, 8.04; N, 5.08. Found, afterdrying in vacuo/P O at 100 C. for 2 /2 hours: C, 56.63; H, 7.88; N,5.00.

Step C.-Preparation of 2,4,5-trihydroxy-a-ethylphenethylaminehydrochloride 2,4,5 tn'methoxy or. ethyl phenethylamine hydrochloride(5.52 g., 0.02 mole), 100 ml. of Br free 48% hydrobromic acid weretreated by the same procedure described for the preparation of thea-methyl analog and a clear amber glassy product was obtained which didnot crystallize.

Analysis.Calcd. for C H O NBrz C, 43.18; H, 5.80; N, 5.04; Br, 28.73.Found, after drying at 140 C. in vacuo/P O for 21 hours: C, 43.84; H,5.89; N, 5.09; Br, 27.95; OCH 0.00.

Chromatography in the same system described for the a-methyl-isomershowed a major component of R, 0.37 and a minor component of R 0.52which appeared to be forming during the chromatography.

EXAMPLE V.SINGLE DOSE PREPARATION CON- TAINING 2,4,5 TRIHYDROXYPHENETHYL- AMINE One gram of 2,4,5 -trihydroxyphenethylamine, madeaccording to the aforementioned journal article, is equally subdividedinto fifty parts and each part Weighing milligrams is placed in a hardelastic capsule. One or two of these capsules may be taken at a time,once a day or if required, up to four times a day.

If the desired clinical response requires larger dosages, largercapsules would be used so that each would contain up to 200 milligrams.

EXAMPLE VI.SINGLE DOSE PREPARATION CON- TAINING 2 AMINO 4,5DIHYDROXY-PHEN- ETHYLAMINE One gram of 2 amino 4,5dihydroxyphenethylamine made according to the aforementioned journalarticle, is equally subdivided into fifty parts and each part weighing20 milligrams is placed in a hard elastic capsule. One or two of thesecapsules may be taken at a time, once a day or if required, up to fourtimes a day.

If the desired clinical response requires larger dosages,

larger capsules would be used so that each would contain up to 200milligrams.

The products of Examples 1 to 4 can be put up in unit dosage form as inExamples 5 and 6.

EXAMPLE VII.-TABLETS CONTAINING 2,4,5- TRIHYDROXYPHENETHYLAMINE One gramof 2,4,5 trihydroxyphenethylamine is combined with conventionaltableting ingredients according to known procedures and the mixture issubdivided into 25 parts. Each part, weighing 40 milligrams iscompressed into a scored tablet so that a fractional tablet may be takenor one or several tablets may be taken at a time.

Tablets containing larger amounts of this active agent may be made up,or one of the other active agents contemplated by this invention may besubstituted.

I claim:

1. A method for the treatment of hypertension which comprisesadministering to a hypertensive patient a hypotensively effective amountof a compound having the formula:

I OHzCHNHz in which R is selected from the group consisting of-OI-I and-NH and R is selected from the group consisting of H, CH and C H or thepharmaceutically acceptable salts thereof.

3. A method for treatment of hypertension, which comprises administeringto a Warm-blooded mammal an effective amount of 2,4,5 trihydroxy amethylphenethylamine or the pharmaceutically acceptable salts thereof.

4. The method of claim 3 wherein said warm-blooded mammal is a human.

References Cited UNITED STATES PATENTS 2,858,312 10/1958 Olin 200570.8

FOREIGN PATENTS 7/1961 Germany.

OTHER REFERENCES Harley-Mason Journal of the Chemical Society (London)for 1953, pp. 200203.

Horner et al., Justus Liebigs Annalen der Chemie, vol. 608, pp. 128-139(1957).

Senoh et al., Journal of the American Chemical Society, vol. 81, pp.6236- 6240 (1959).

Hazard et al., Chemical Abstracts, vol. 55, column 20193(c) and SubjectIndex for Volume 55, p. 18405 (1961).

ALBERT T. MEYERS, Primary Examiner I. GOLDBERG, Assistant Examiner

